Eukaryotic DNA is packaged into chromatin in a precise and highly regulated manner. This level of organisation is fundamental to many processes in the cell including replication, repair recombination, chromosomal segregation and transcriptional regulation. DNA is wrapped around the core histone octamer (H2A, H2B, H3 and H4) to form nucleosomes, which are the basic repeating units of chromatin. The crystal structure of the nucleosome has been solved and this has provided much information but there is still a great deal to learn about the mechanisms by which distinct functional domains of chromatin are formed and maintained. The most important changes in chromatin structure are thought to be influenced by post-translational modifications of N-terminal tails of the histones, which protrude from the nucleosome. These are highly basic when unmodified and interact with negatively charged DNA phosphate backbone. Specific amino acids within these tails are targets for a variety enzymes which can produce diverse modifications such as acetylation, methylation, phosphorylation, poly(ADP-ribosylation), and ubiquination. Acetylation is thus far the most widely studied and is catalysed by histone acetyltransferases (HATs) and involves substitution of the ε-amino group of specific lysines.
This leads to a more acidic residue and an overall decreased affinity for DNA by the histone octamer. It appears that the histone tails also mediate interactions between nucleosomes to form higher order chromatin structures and they could be disrupted by acetylation. The packaging of DNA into nucleosomal arrays presents a major physical obstacle to the transcriptional machinery when trying to gain access to the DNA template and there is strong evidence that unwinding of nucleosomes due to the acetylation of histone tails plays a fundamental role in the activation of gene transcription. In contrast to histone acetylation in transcriptional activation, enzymes which remove these modifications would be expected to have an important role in down-regulation and gene silencing. This has indeed been shown to be the case and recent studies have also implicated abnormal histone deacetylase function in a number of human cancers.
To date eight histone deacetylases have been characterised which may broadly divided into two related classes which share homology through their deacetylase domains with yeast histone deacetylases Rpd3 and Hda1. Class II HDACs 4, 5 and 7 may be differentiated from the Class I HDACs as they contain an additional N-terminal, non catalytic, region which is homologous to a protein previously characterized as a co-repressor, MEF2-Interacting Transcription Repressor (MITR/HDRP).
Zhou et al (PNAS, 98(19):10572-10577, 2001) purports to disclose the sequence of histone deacetylase HDAC9. However, the protein disclosed in the paper is incomplete and the level of deacetylase activity reported in the paper is below the negative control.